One in five women worldwide carries latent tuberculosis infection (LTBI), and 3 million are diagnosed with active tuberculosis (TB) each year. Women are most likely to convert from latent to active TB during and immediately after pregnancy. The immunologic conditions responsible for this phenomenon are not understood. This knowledge gap impairs our ability to develop effective LTBI screening tests for pregnant women and accurately predict which patients should be targeted for TB prevention. The need is urgent. TB is a leading cause of maternal mortality, especially among HIV-infected women. Maternal TB is also an important children's health issue: Maternal TB more than doubles the risk of mother-to-child HIV transmission and significantly increases the risk of mortality for the newborn and other young children living in the household. Our recent research shows that pregnant women with LTBI have diminished IFN-gamma response to Mycobacterium tuberculosis (MTB)-specific antigens during the 3rd trimester and return to baseline 3-6 months postpartum. We hypothesize that the increase in regulatory T cells (Treg) during pregnancy reduces multi-functional CD4+ T-cell production of Th1 cytokines in response to MTB antigens, which increases the risk of progression to active TB. In partnership with BJ Medical College and the National Institute for Research of Tuberculosis/ intramural NIH-supported ICER program in India, we propose a longitudinal cohort study to describe the timing, extent, and causes of these immune changes. We will also follow women prospectively and identify immunological correlates of TB reactivation. Pregnant women with LTBI will be enrolled from the antenatal clinic in Pune, India, during their 2nd trimester with additional visits at 3rd trimester, delivery 3, 6, and 12 months postpartum. At each visit, we will screen for active TB. We will also collect blood samples for IFN-gamma release assays, cytokine assays, flow cytometry, and gene transcription studies. Our first aim is to quantify the extent and timing of the suppression of Th1 cytokine production in response to MTB-specific antigens, a process that likely contributes to the reactivation of LTBI during pregnancy. By including both HIV-infected and HIV-uninfected women, we will further explore how HIV affects this suppression. Our second aim is to describe the cellular mechanisms underlying the suppression, which we believe is related to increase Treg frequency in pregnancy. Our third aim is to use cytokine and RNA expression profiles to identify a biosignature associated with progression to active TB. These findings will provide a comprehensive picture of the immune changes of pregnancy that compromise a woman's ability to contain MTB in its latent form. The study will also provide a path towards identifying a diagnostic biomarker to enable clinicians to identify and treat pregnant women at highest risk of developing active TB.